Heart malfunction or failure after myocardial infarction (Ml) is a leading cause of disability and death. The success of endothelial or cardiac stem cells to improve heart recovery after ischemic damage holds great promise for cell-based therapies to treat myocardial infarction. We recently found that application of embryonic endothelial progenitor cells (eEPCs) after infarction in the mouse or pig increases capillary density and improves heart performance. However, the reasons for heart recovery after cell therapy remain unclear. A broad spectrum of progenitor cells show beneficial effects, but participation of donor cells as functional entities in host tissue is often transient, or relatively low, hardly explaining the substantial improvement in whole organ function. This raises the possibility that endothelial progenitors - besides building new vessels - improve tissue recovery in ways that are poorly understood. Consistent with this notion, we found that the benefits of eEPC application are already evident 24 hours after transplantation suggesting an acute cardioprotective effect mediated by paracrine interactions between eEPCs and host tissue. Using genome-wide expression profiling and bioinformatics, we identified most of the eEPC-secreted factors and we placed them in 7 functional groups. Further comparison with mature endothelial cells revealed that one group, consisting of wnt-pathway modulators, is highly specific to the eEPC population. To determine if wnt-pathway modulation contributes to the stem-cell cardioprotection effects, we will: (1) investigate how wnt-signaling changes in acute or chronic heart ischemia;(2) analyze how transplanted EPCs modulate wnt-signaling in the injured heart;and (3) identify the cellular and molecular mechanisms of the EPC-mediated cardioprotection. These studies focus on the fundamental issue of how stem cells help the heart to recover after myocardial infarction. This knowledge will help shape future therapeutic strategies to treat heart injuries.